Leptin enhances NMDA-induced spinal excitation in rats: A functional link between adipocytokine and neuropathic pain

Pain. 2011 Jun;152(6):1263-71. doi: 10.1016/j.pain.2011.01.054. Epub 2011 Mar 4.

Abstract

Recent studies have shown that leptin (an adipocytokine) played an important role in nociceptive behavior induced by nerve injury, but the cellular mechanism of this action remains unclear. Using the whole-cell patch-clamp recording from rat's spinal cord slices, we showed that superfusion of leptin onto spinal cord slices dose-dependently enhanced N-methyl-d-aspartate (NMDA) receptor-mediated currents in spinal cord lamina II neurons. At the cellular level, the effect of leptin on spinal NMDA-induced currents was mediated through the leptin receptor and the JAK2/STAT3 (but not PI3K or MAPK) pathway, as the leptin effect was abolished in leptin receptor-deficient (db/db) mice and inhibited by a JAK/STAT inhibitor. Moreover, we demonstrated in naïve rats that a single intrathecal administration of leptin enhanced spontaneous biting, scratching, and licking behavior induced by intrathecal NMDA and that repeated intrathecal administration of leptin elicited thermal hyperalgesia and mechanical allodynia, which was attenuated by the noncompetitive NMDA receptor antagonist MK-801. Intrathecal leptin also upregulated the expression of NMDA receptors and pSTAT3 within the rat's spinal cord dorsal horn, and intrathecal MK-801 attenuated this leptin effect as well. Our data demonstrate a relationship between leptin and NMDA receptor-mediated spinal neuronal excitation and its functional role in nociceptive behavior. Since leptin contributes to nociceptive behavior induced by nerve injury, the present findings suggest an important cellular link between the leptin's spinal effect and the NMDA receptor-mediated cellular mechanism of neuropathic pain. A functional link is demonstrated between leptin, an adipocytokine, and the cellular mechanisms of neuropathic pain via enhancement of function and expression of spinal N-methyl-d-aspartate receptors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • Behavior, Animal / drug effects
  • Dizocilpine Maleate / therapeutic use
  • Drug Interactions
  • Electric Stimulation / methods
  • Excitatory Amino Acid Agonists / pharmacology*
  • Excitatory Amino Acid Antagonists / therapeutic use
  • Hyperalgesia / drug therapy
  • Hyperalgesia / physiopathology
  • In Vitro Techniques
  • Leptin / pharmacology*
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Mice
  • Mice, Knockout
  • N-Methylaspartate / pharmacology*
  • Neuralgia / chemically induced
  • Neuralgia / physiopathology
  • Pain Measurement
  • Patch-Clamp Techniques / methods
  • Physical Stimulation / adverse effects
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Leptin / deficiency
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • STAT3 Transcription Factor / metabolism
  • Sensory Receptor Cells / drug effects*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Spinal Cord / cytology
  • Spinal Cord / drug effects*
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Leptin
  • NR1 NMDA receptor
  • Receptors, Leptin
  • Receptors, N-Methyl-D-Aspartate
  • STAT3 Transcription Factor
  • N-Methylaspartate
  • Dizocilpine Maleate